Correction: Corrigendum: The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function

Clutton, Genevieve; Xu, Yanxin; Baldoni, Pedro L.; Mollan, Katie R.; Kirchherr, Jennifer; Newhard, William; Cox, Kara S.; Kuruc, JoAnn; Kashuba, Angela D. M.; Barnard, Robert C.; Archin, Nancie M.; Gay, Catherine; Hudgens, Michael G.; Margolis, Don; Goonetilleke, Nilu

doi:10.1038/srep34430

Sci Rep

2016

DOI: 10.1038/srep34430

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Correction: Corrigendum: The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function

Genevieve Clutton¹,

Yanxin Xu²,

Pedro L. Baldoni³

et al.

Abstract: Scientific Reports 6: Article number: 30749; published online: 02 August 2016; updated: 03 October 2016 The Acknowledgements section in this Article is incomplete. “We thank all the study participants. For technical assistance we thank Kuo Yang and members of the UNC Clinical Trials Unit, the UNC CFAR Immunology Core and the UNC Flow Cytometry Core Facility.

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Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure

Clutton

Jones

2018

Front. Immunol.

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Antiretroviral therapy regimens durably suppress HIV replication, but do not cure infection. This is partially attributable to the persistence of long-lived pools of resting CD4+ T-cells harboring latent replication-competent virus. Substantial clinical and pre-clinical research is currently being directed at purging this viral reservoir by combining pharmacological latency reversal with immune effectors, such as HIV-specific CD8+ T-cells, capable of eliminating reactivated targets—the so-called “shock-and-kill” approach. However, several studies indicate that the latency-reversing agents (LRAs) may affect CD8+ T-cell function. The current review aims to frame recent advances, and ongoing challenges, in implementing “shock-and-kill” strategies from the perspective of effectively harnessing CD8+ T-cells. We review and contextualize findings indicating that LRAs often have unintended impacts on CD8+ T-cell function, both detrimental and beneficial. We identify and attempt to bridge the gap between viral reactivation, as measured by the detection of RNA or protein, and bona fide presentation of viral antigens to CD8+ T-cells. Finally, we highlight factors on the effector (CD8+) and target (CD4+) cell sides that contribute to whether or not infected-cell recognition results in killing/elimination. These perspectives may contribute to an integrated view of “shock-and-kill,” with implications for therapeutic development.

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Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure

Clutton

Jones

2018

Front. Immunol.

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In Vitro Exposure to Prostratin but Not Bryostatin-1 Improves Natural Killer Cell Functions Including Killing of CD4+ T Cells Harboring Reactivated Human Immunodeficiency Virus

et al. 2018

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In the attempt of purging the HIV-1 reservoir through the “shock-and-kill” strategy, it is important to select latency-reversing agents (LRAs) devoid of deleterious effects on the antiviral function of immune effector cells. Here, we investigated two LRAs with PKC agonist activity, prostratin (PRO) and bryostatin-1 (BRY), for their impact on the function of natural killer (NK) cells, the major effectors of innate immunity whose potential in HIV-1 eradication has emerged in recent clinical trials. Using NK cells of healthy donors, we found that exposure to either PRO or BRY potently activated NK cells, resulting in upmodulation of NKG2D and NKp44 activating receptors and matrix metalloprotease-mediated shedding of CD16 receptor. Despite PRO and BRY affected NK cell phenotype in the same manner, their impact on NK cell function was diverse and showed considerable donor-to-donor variation. Altogether, in most tested donors, the natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells were either improved or maintained by PRO, while both activities were impaired by BRY. Moreover, we analyzed the effect of these drugs on the capacity of treated NK cells to kill autologous latently infected CD4+ T cells reactivated via the same treatment. First, we found that PRO but not BRY increased upmodulation of the ULBP2 ligand for NKG2D on reactivated p24+ cells. Importantly, we showed that clearance of reactivated p24+ cells by NK cells was enhanced when both targets and effectors were exposed to PRO but not to BRY. Overall, PRO had a superior potential compared with BRY as to the impact on key NK cell functions and on NK-cell-mediated clearance of the HIV-1 reservoir. Our results emphasize the importance of considering the effects on NK cells of candidate “shock-and-kill” interventions. With respect to combinative approaches, the impact on NK cells of each LRA should be re-evaluated upon combination with a second LRA, which may have analogous or opposite effects, or with immunotherapy targeting NK cells. In addition, avoiding co-administration of LRAs that negatively impact ADCC activity by NK cells might be essential for successful application of antibodies or vaccination to “shock-and-kill” strategies.

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Correction: Corrigendum: The differential short- and long-term effects of HIV-1 latency-reversing agents on T cell function

Cited by 2 publications

References 0 publications

Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure

Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure

In Vitro Exposure to Prostratin but Not Bryostatin-1 Improves Natural Killer Cell Functions Including Killing of CD4+ T Cells Harboring Reactivated Human Immunodeficiency Virus

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